PROJECT SUMMARY/ABSTRACT Chronic exposure of the general population to low-doses of toxic metals, including lead, cadmium, and manganese, from contaminated food and drinking water is widespread in the United States, with African Americans being more exposed than their white counterparts. This racial disparity in exposure may contribute to the unequal burden of disease experienced by African Americans, including the development of uterine fibroids. These smooth muscle uterine tumors develop in more than 80% of African American women by age 50 and are associated with substantial morbidity. Few risk factors for this disease have been identified that are amenable to intervention, motivating the need to investigate the role of environmental factors. In addition, given the difficulty in avoiding exposure to toxic metals that are ubiquitous in the environment, understanding behavioral and biologic factors, including diet and iron stores, involved in the body's uptake of these chemicals is critical for prevention. However, few human studies have been conducted on these factors that may influence the uptake and absorption of toxic metals, particularly among reproductive-age women, the majority of whom have inadequate dietary intakes of iron, zinc, and calcium, and for whom menstrual blood loss is a major contributor to iron deficiency. In addition, prior human studies of metals and uterine fibroids have yielded contradictory results, likely due to the limitations of the study designs employed. The central hypotheses in this proposal are that 1) common deficiencies in the dietary intake of iron, calcium, and zinc as well as the depletion of iron stores from heavy menstrual bleeding, increase the body's uptake of lead, cadmium and manganese in women, and 2) these toxic metals increase uterine fibroid risk given the mutagenic and hormonal actions exhibited in vivo and in vitro. To test these hypotheses, the proposed research will build on an established cohort of nearly 1,700 young, African American women using data and archived biosamples from the Study of Environment, Lifestyle & Fibroids (SELF), a 5-year prospective study of fibroids funded by the National Institute of Environmental Health Sciences (ZIAES049013, D. Baird, Principal Investigator). Archived whole blood samples from enrollment will be analyzed for lead, cadmium, and manganese and stored serum samples will be measured for biomarkers of body iron stores, ferritin and transferrin receptor. These biomarker data will be linked to questionnaire data on dietary intake and heavy menstrual bleeding as well as to ultrasound data on fibroids collected every 20 months over 5 years to accomplish the following aims: 1) to determine the extent to which deficiencies in dietary intake of essential nutrients iron, calcium, and zinc are associated with altered blood concentrations of lead, cadmium, and manganese; 2) to determine the associations between low body iron stores, heavy menstrual bleeding, and lead, cadmium, and manganese concentrations; and 3) to determine the associations between blood lead, cadmium, and manganese concentrations at enrollment and uterine fibroid incidence over a 5-year period. The research and accompanying career development plan proposed in this NIH Pathway to Independence Award application will allow Dr. Upson to achieve her long-term career goal as a nurse scientist to answer important research questions that bridge the fields of women's reproductive health and environmental health to ultimately inform feasible interventions to improve the health of reproductive-age women. The K99 mentored- phase of the award will take place within the Intramural Research Program at the National Institute of Environmental Health Sciences, an institute at the vanguard of environmental health research. Dr. Upson will receive mentorship from Drs. Donna Baird, Janet Hall, and Erik Tokar, eminent scholars in uterine fibroid research, reproductive endocrinology, and metals toxicology, respectively. Additional mentoring will be provided by her advisory committee consisting of Dr. Michelle Mendez, an expert in nutritional epidemiology, and Dr. Elizabeth Corwin, who has expertise in R01 grantsmanship and the academic job search process as an established nurse scientist. The mentorship component will be complemented by structured training activities, consisting of coursework, directed readings, attendance at workshops, seminars, and national meetings, and career development activities to address key areas of professional growth that will promote the transition to independence. From the provision of this mentorship and the completion of structured training activities, Dr. Upson will achieve her short-term goals which include gaining a proficiency in toxicology, reproductive endocrinology, and nutrition, and integrating this knowledge into her existing nursing knowledge and epidemiologic skill set so as to conduct novel research during the K99 and R00 phases of the award. This will allow Dr. Upson to contribute critical information on behavioral and biologic factors involved in the body's uptake of metals as well to conduct the first prospective study of toxic metals and uterine fibroid risk during the R00 independent phase. The conduct of this innovative research and training will not only facilitate the successful launch of the candidate's independent research career as a nurse scientist, but will inform future interventions to prevent disparate exposure to toxic metals, reduce the burden of disease, and improve quality of life, in alignment with the research priorities of the National Institute of Nursing Research.